Quantitative Assessment of Mass Flow Boundaries in Continuous Twin-screw Granulation.

In pharmaceutical manufacturing, there is an increasing interest in continuous manufacturing. As an example for fast continuous processes in general of considerable complexity, this study was focussed on improving the understanding of twin-screw wet granulation. The impact of the liquid-to-solid (L/S) mass flow ratio on product quality (granules) as well as on downstream process operations (tableting) was investigated in detail. Initially two methods were used to define L/S ratio boundaries for the granulation regime in twin-screw wet granulation. It was shown that the first method, which is based on measuring the wet granule mass flow variation, can be used to define the upper L/S ratio boundary of the granulation regime. The second method, based on measuring the granule size distribution, can be used to define the lower L/S ratio boundary of the regime. Using these methods, the granulation regime for different formulations could be established. This information was then used to show that the formulation could be optimised such that the process is more robust (i.e. wider L/S ratio boundaries for the granulation regime). Also it could be used to optimise the formulation considering further downstream processing such as drying (using as little water as possible to reduce drying efforts) or tableting (obtain granules with optimised tableting properties). Preferably, the process should be performed close to the lower L/S ratio boundary of the granulation regime. In summary, these tools enabled the quantitative establishment of granulation regime boundaries in a twin-screw wet granulation process and can be used to optimise formulation and to create a robust process. Analogies to other continuous processes in completely different applications can be conceived.

Safety and robustness of coated pellets: self-healing film properties and storage stability.

PURPOSE: Aim of the study was to verify the safety of chlorpheniramine maleate pellets, coated with blends of poly(vinyl acetate) and poly(vinyl alcohol)-poly(ethylene glycol) graft copolymer. Therefore, the impact of mechanical forces and storage conditions on the drug release was investigated. RESULTS: Similar release profiles before and after compression of the pellets to tablets underlined the high film robustness. A damage of the film coat with a razor blade resulted in a premature release, but without a burst. After a similar damage with a needle, the release profile remained almost unchanged, which indicated a swelling based self repair mechanism of the film. Additional studies were dedicated to the storage stability at three different conditions. A slightly delayed release was obtained after 6 months storage at 25 degrees C and a marginally accelerated release was measured after storage at elevated temperatures. No drug migration into the coating layer was detected during storage by confocal Raman microscopy. (1)H-NMR analysis during storage demonstrated, that no polymer or drug degradation had occurred and the plasticizer concentration remained constant. CONCLUSION: The polyvinyl based coating blend for modified release pellets demonstrated a high safety, due to their high robustness and compressibility as well as their satisfying storage stability.

Simplified end-to-end continuous manufacturing by feeding API suspensions in twin-screw wet granulation.

This study focussed on investigating the coupling of continuous manufacturing of drug substance and continuous manufacture of drug product. An important step in such an integrated end-to-end continuous manufacturing was envisioned by dosing the API as suspension into a twin-screw wet granulation process. To achieve this goal, a model drug substance (ibuprofen) was fed as a concentrated aqueous suspension (50% w/w) into a twin-screw granulator and compared against traditional solid feeding of the model drug substance to meet a target ibuprofen load of 60% w/w in the formulation. Granulation and compaction behaviour were evaluated to determine the impact of feeding API as suspension in twin-screw wet granulation on the critical quality attributes of the drug product. It was demonstrated that the ibuprofen suspension feed is comparable with the ibuprofen dry blend feed in twin-screw wet granulation. Next to enabling end-to-end continuous manufacturing, API suspension feed in twin-screw wet granulation could afford a number of additional advantages including manufacturing efficiency by removing the drying step for API, or overcoming processing issues linked to the bulk properties of the API powder (e.g. flowability).

Impact of fill-level in twin-screw granulation on critical quality attributes of granules and tablets.

In a previous study a change of the fill-level in the barrel exerted a huge influence on the twin-screw granulation (TSG) process of a high drug loaded, simplified formulation. The present work investigated this influence systematically. The specific feed load (SFL) indicating the mass per revolution as surrogate parameter for the fill-level was applied and the correlation to the real volumetric fill level of an extruder could be demonstrated by a newly developed method. A design of experiments was conducted to examine the combined influence of SFL and screw speed on the process and on critical quality attributes of granules and tablets. The same formulation was granulated at constant liquid level with the same screw configuration and led to distinctively different results by only changing the fill-level and the screw speed. The power consumption of the extruder increased at higher SFLs with hardly any influence of screw speed. At low SFL the median residence time was mainly fill-level dependent and at higher SFL mainly screw speed dependent. Optimal values for the product characteristics were found at medium values for the SFL. Granule size distributions shifted from mono-modal and narrow shape to broader and even bimodal distributions of larger median granule sizes, when exceeding or falling below a certain fill-level. Deviating from the optimum fill-level, tensile strength of tablets decreased by about 25% and disintegration times of tablets increased for more than one third. At low fill-levels, material accumulation in front of the kneading zone was detected by pressure measurements and was assumed to be responsible for the unfavored product performance. At high fill-levels, granule consolidation due to higher propensity of contact with the result of higher material temperature was accounted for inferior product performance. The fill-level was found to be an important factor in assessment and development of twin-screw granulation processes as it impacted process and product attributes enormously.

How Deformation Behavior Controls Product Performance After Twin Screw Granulation With High Drug Loads and Crospovidone as Disintegrant.

This study addresses the quantitative influence of 12 different materials (active pharmaceutical ingredients and excipients as surrogate active pharmaceutical ingredients) on the critical quality attributes of twin screw granulated products and subsequently produced tablets. Prestudies demonstrated the significant influence of the chosen model materials (in combination with crospovidone) on the disintegration behavior of the resulting tablets, despite comparable tablet porosities. This study elucidates possible reasons for the varying disintegration behavior by investigating raw material, granule, and tablet properties. An answer could be found in the mechanical properties of the raw materials and the produced granules. Through compressibility studies, the materials could be classified into materials with high compressibility, which deform rather plastically under compression stress, and low compressibility, which display breakages under compression stress. In general, and apart from (pseudo)-polymorphic transformations, brittle materials featured excellent disintegration performance, even at low resulting tablet porosities <8%, whereas plastically deformable materials mostly did not reveal any disintegration. These findings must be considered in the development of simplified formulations with high drug loads, in which the active pharmaceutical ingredient predominantly defines the deformation behavior of the granule.

Modulating pH-independent release from coated pellets: effect of coating composition on solubilization processes and drug release.

The aim of the study was to clarify the influences of three coating parameters on the drug release from chlorpheniramine maleate (CPM) pellets, coated with blends of poly(vinyl acetate) (PVAc) and poly(vinyl alcohol)-poly(ethylene glycol) (PVA-PEG) graft copolymer. A central composite design was implemented to investigate the effect of the polymer blend ratio, the film coat thickness and the plasticizer concentration on the drug release. The solubilization inside the pellets was monitored by EPR spectroscopy. The blending ratio of both the polymers and the film thickness were found to have a major influence on the drug release and the solubilization speed, in contrast to the plasticizer concentration. A pH-independent release profile was adjustable via modulating the polymer blend ratio and the coating thickness. A mathematical model was developed, providing a good predictability of the release profile, based on the film coat composition. This model offers the possibility to achieve a defined drug-release profile by selective adaptation of the film coat composition, in view of process times, feasibility or polymer costs.

Changes of the properties in the upper layers of human skin on treatment with models of different pharmaceutical formulations - an ex vivo ESR imaging study.

The noninvasive method of spectral-spatial electron spin resonance imaging (ESRI) was used to obtain a polarity map of human skin. The spin probes TEMPO, TEMPOL, and CAT-1, which are considered to act as drug representatives, were applied as reporter molecules. The polarity in skin layers was described by means of the changes of the hyperfine splitting constant A(iso), which itself is a reflection of interactions at a molecular level, and the effect of polarity on the spatial distribution of spin probes in skin samples was studied. Analyses of ESR tomograms of two-phase systems finalized in a simplified description for the empiric interpretation of values of the isotropic hyperfine coupling constants A(iso) of spin probes in different layers of human skin. The simplified statement provides values for the probability of interactions of water molecules with the NO group of spin probes. This allows conclusions concerning the state of hydration of the spin probes in different layers of the skin and introduces the spatial polarity function as additional and valuable information for existing skin models.

New insight into modified release pellets - Internal structure and drug release mechanism.

The aim of the study was to explore the drug release mechanism from pellets, coated with blends of poly(vinyl acetate) (PVAc) and polyvinyl alcohol-polyethylene glycol graft copolymer (PVA-PEG). Water influx and drug solubilization inside the pellets were investigated in correlation to drug release. The highly soluble drug Chlorpheniramine maleate (CPM) was used as a model compound. Modified release pellets were manufactured by fluid bed drug layering and film coating of starter beads. The pellets were characterized using cross section EDX mapping, confirming location and homogeneity of the different layers. A film coat of 23%, containing PVAc/PVA-PEG in 9:1 ratio, resulted in a sigmoid shaped release curve with 2 h lag-time, followed by 3 h of continuous drug release. Using NMR analysis, water influx and drug solubilization inside the pellets were detected within 20 min. Additionally, dissolution of PVA-PEG after several minutes and drug release after the lag-time were measurable. A fast water influx into PVAc/PVA-PEG film coated pellets did not result in a fast drug release. Despite a fast drug solubilization within the pellets, drug release was initiated after 2 h, suggesting a one way stream of water during the observed lag-time.

In vivo ESR studies on subcutaneously injected multilamellar liposomes in living mice.

PURPOSE: An innovative, noninvasive, low-frequency electron spin resonance (ESR) spectroscopy method was applied and adapted to investigate the integrity of multilamellar liposomes from hydrogenated phospholipids after subcutaneous injection in living mice. Moreover, the fate of the injected liposomal preparations was examined, as well as the possibility to achieve a depot effect. METHODS: Highly concentrated solutions of the spin probe 2,2,6,6-tetramethyl-4-trimethylammoniumpiperidine-1-oxyl-iodide (CAT-1; 138 mM) were encapsulated in liposomes. They were characterized by laser diffraction, and the liberation of spin probe was investigated by ESR spectroscopy. RESULTS: Line shape changes allowed the differentiation between encapsulated and released CAT-1 after subcutaneous injection of liposomes. Multilamellar liposomes form a local depot at the site of injection. A sustained release of the spin probe from the depot was monitored by means of ESR. Whereas 40% of the spin probe was released within the first 96 h after administration, 60% remained in intact liposomes under the skin. No depot formation could be observed after injection of CAT-1 solutions, but a fast signal decrease due to systemic distribution and bioreduction of the nitroxide spin probe. CONCLUSIONS: Noninvasive analysis of liposomal integrity in living animals was successfully accomplished using a new L-Band ESR spectroscopy method. The liberation of CAT-1 from liposomes in vitro and in vivo was monitored by changes in the lineshape of ESR spectra and Heisenberg spin exchange. The significance of liposomal integrity for the formation of a localized drug depot effect was proved.